In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies – a physician survey and a medical records review (MRR) – were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice.
Trang 1R E S E A R C H A R T I C L E Open Access
Panitumumab use in metastatic colorectal
from a Europe-wide physician survey and
medical records review
J Han van Krieken1*, George Kafatos2, James Bennett2, Laurent Mineur3, Ji ří Tomášek4
, Etienne Rouleau5, Pavel Fabian4, Giovanna De Maglio6, Pilar García-Alfonso7, Giuseppe Aprile6, Parijan Parkar2, Gerald Downey8, Gaston Demonty9and Jörg Trojan10
Abstract
Background: In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior
confirmation ofRAS wild-type mutation status Two studies – a physician survey and a medical records review (MRR)– were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associatedRAS testing requirements in clinical practice
Methods: Both studies enrolled participants from nine European countries and were carried out in three
consecutive rounds Rounds 1 and 2 (2012–2013) examined KRAS (exon 2) testing only; the results have been published in full previously Round 3 (2014–2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiringKRAS alone to requiring full RAS testing For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab
to patients with mCRC in the previous 6 months For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients’ records
Results: In Round 3, 152 oncologists and 131 patients’ records were included in the physician survey and MRR, respectively In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that
panitumumab should only be prescribed inRAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants
in Rounds 1 and 2, responding to the same question aboutKRAS testing In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmedKRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only) Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only
Conclusions: Physicians’ adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, fromKRAS to RAS wild-type mCRC Additionally, this study
demonstrates the uptake of fullRAS testing among the majority of oncologists and pathologists
Keywords: Panitumumab, Metastatic colorectal cancer, mCRC,RAS, Physician survey, Medical records review
* Correspondence: Han.vanKrieken@radboudumc.nl
1 Radboud University Medical Center, Nijmegen, Netherlands
Full list of author information is available at the end of the article
© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2The epidermal growth factor receptor (EGFR) is a cell
surface protein that has become an important
thera-peutic target in colorectal cancer (CRC) [1] Two
mono-clonal antibodies that target the extracellular domain of
the EGFR have been developed: cetuximab (Erbitux),
which is a recombinant immunoglobulin G1
mouse–hu-man chimeric anti-EGFR monoclonal antibody (mAb),
and panitumumab (Vectibix), a recombinant, fully
hu-man immunoglobulin G2 anti-EGFR mAb [1, 2]
Anti-EGFR therapy (treatment with cetuximab or
panitumu-mab) has been shown to be effective in metastatic CRC
(mCRC) [3–6] Initially, patients with tumours that had
mutations of exon 2 of theKRAS oncogene were found to
be resistant to treatment with anti-EGFR mAbs [3, 7, 8]
Further studies provided evidence that additional
muta-tions beyond KRAS exon 2 occurring in the wider RAS
family of oncogenes, specifically in exons 3 and 4 ofKRAS
and exons 2, 3 and 4 ofNRAS, are also predictive of a lack
of response to anti-EGFR therapy [9–13]
Panitumumab was first approved in the European
Union (EU) in December 2007 as monotherapy for the
treatment of patients with mCRC and confirmed
wild-type KRAS tumour status after failure of
fluoropyrimi-dine-, oxaliplatin- or irinotecan-containing
chemother-apy [3, 14] However, in November 2011, the approved
licence for panitumumab was extended to cover its use
as a first-line agent in combination with 5-fluorouracil/
folinic acid + oxaliplatin (FOLFOX) chemotherapy and
as second line in combination with 5-fluorouracil/folinic
acid + irinotecan (FOLFIRI) chemotherapy, again
re-stricted to patients with confirmed wild-type KRAS
tumour status [7, 15] In June 2013, EU treatment
guide-lines changed to recommend that panitumumab should
be prescribed to patients with mCRC and wild-typeRAS
tumour status (exons 2, 3, 4 of KRAS and NRAS),
which should be confirmed prior to treatment
initi-ation [16, 17] The current label for panitumumab
in-cludes a contraindication for its use in combination
with oxaliplatin-containing chemotherapy in patients
with mutant or unknown RAS tumour status (or
KRAS status before June 2013) [16]
Two studies – a physician survey and a medical
re-cords review (MRR)– were initiated in Europe in 2012
to evaluate physicians’ awareness of the correct
thera-peutic indication for panitumumab and to establish if it
was being prescribed in accordance with this indication,
which is to patients with mCRC and confirmed
wild-type KRAS tumour status prior to treatment with
pani-tumumab The studies were carried out in three
con-secutive rounds; the results of the first two rounds of
both studies have been published previously [18] Overall
in Rounds 1 and 2 of the physician survey, 298 (99.0%)
of 301 physicians responded correctly that panitumumab
should be administered only to patients with confirmed KRAS wild-type tumours In Rounds 1 and 2 of the MRR study, 299 (97.7%) of 306 patients reportedly had confirmed wild-typeKRAS status before the initiation of panitumumab treatment Of 85 patients who were pre-scribed panitumumab with concurrent oxaliplatin-containing chemotherapy in Rounds 1 and 2 of the MRR, 83 (97.6%) had confirmed wild-type KRAS status before the initiation of treatment [18]
The results of the third round of the physician survey and MMR, which focused on full RAS testing, are pre-sented here The primary objective of Round 3 of the physician survey was to assess physicians’ knowledge of the updated indication for panitumumab treatment, fol-lowing the changes to the label modifying its use from KRAS wild-type to RAS wild-type mCRC only Similarly, for Round 3 of the MRR, the main aim was to estimate the prevalence of full RAS testing in the routine clinical management of patients being prescribed panitumumab
Methods
Physician survey and MRR overview
The detailed methodology of Rounds 1 and 2 (assessing KRAS only) for both the physician survey and MRR, conducted from 2012 to 2013, has been published in full previously [18]
Rounds 3 of the physician survey and the MRR were carried out from September 2014 to November 2014 and September 2014 to June 2015, respectively Physi-cians from the following nine European countries were invited to participate in the studies: Belgium, Czech Republic, Denmark, France, Germany, Italy, Spain, the Netherlands and Sweden
For Round 3 of both studies, the following data sources were used to select a random sample of poten-tial participants: (a) a medical marketing database pro-vided by a healthcare industry provider (Cegedim S.A., Boulogne-Billancourt, France), filtered by specialty, and (b) a list of CRC physicians provided by local affiliates of the study sponsor (Amgen Ltd., Uxbridge, UK) Round 3
of the MRR was carried out by Amgen Ltd and Round 3
of the physician survey was carried out by a separate in-dustry provider (Adelphi Research, Bollington, UK)
Eligibility criteria for the physician survey
Practising oncologists were included in Round 3 of the physician survey if they had treated at least three new or continuing patients with mCRC in the 3 months imme-diately preceding their invitation to participate in the survey, and only if they had prescribed panitumumab at least once during the previous 6 months Potential par-ticipants were excluded if they had previously taken part
in either Round 1 or Round 2 of the survey
Trang 3Eligibility criteria for the MRR
Practising oncologists were included in Round 3 of the
MRR if they had treated at least three new or continuing
patients with mCRC in the 3 months immediately prior
to receiving their invitation to participate In addition,
oncologists were only eligible if they had prescribed a
first dose of panitumumab to treat a new patient with
mCRC in the preceding 6 months Again they were
ex-cluded if they had already taken part in either Round 1
or Round 2 of the MRR In addition, only one oncologist
per participating medical centre was permitted to
par-ticipate in the MRR, in each round of the study
Patients were eligible to be included in the MRR by
their oncologist if they had received their first dose of
panitumumab during the 6-month period before the
time at which medical records were accessed for the
study As with participating oncologists, patients were
excluded from the MRR if they had taken part in Rounds
1 or 2 Patients were also excluded if they were
partici-pating in an experimental clinical trial at the time of
re-ceiving panitumumab
Data collection
In Round 3 of the physician survey, telephone interviews
were conducted with eligible oncologists using a
stan-dardised questionnaire (see Additional file 1 for
inter-view guide) and following consistent data-collection
procedures
For each oncologist included in the MRR, the relevant
anonymised information for eligible patients who had
received their first dose of panitumumab was abstracted from their medical records using standardised forms The oncologists were also asked to identify the path-ology centre that performed the RAS (or KRAS) testing Further information was then collected and reported by the pathologists at these centres, again using a standar-dised questionnaire
Statistical analysis
The data analysis was descriptive for both the physician survey and MRR For the categorical study endpoints, the count and proportion (%) in each category, based on the appropriate denominator, were calculated The 95% confidence intervals were calculated for the proportions based on a normal approximation to the binomial distribution
Results
Physician survey
Across the nine participating European countries, a total
of 3687 oncologists were contacted in Round 3 and sent
an eligibility screening questionnaire Of those approached, 217 oncologists responded to the screening questionnaire, resulting in a 5.9% response rate; of those responding, 152 (70.0%) were found to be eligible and subsequently participated in the survey (Fig 1) The ma-jority of participating oncologists were based in Germany, France, Italy and Spain Comparatively few oncologists participated from the Czech Republic,
Fig 1 Physician disposition for the a) physician survey and b) medical records review studies a For Round 1, physicians were randomly selected for inclusion from a broad sampling list not filtered by speciality A more targeted sampling of physicians filtered by speciality and based on the study eligibility criteria was used in Rounds 2 and 3
Trang 4Belgium, the Netherlands, Denmark and Sweden
(Table 1)
In Round 3, the institutions with the highest number
of participating oncologists were university and
teach-ing/training hospitals (n = 70; 46.1%), followed by
gen-eral or regional hospitals (n = 42; 27.6%) and private
clinics and hospitals (n = 25; 16.4%) Among the study
participants, the median duration of experience as a
practising oncologist specialising in mCRC was 12.0 years
(interquartile range [IQR] 8.0–18.0 years) and the
median number of patients with mCRC who they had treated in the 3 months before their participation in the survey was 40.0 (IQR 30.0–60.0) (Table 1)
In Round 3, all 152 oncologists correctly identified that RAS testing should be performed prior to the initiation of panitumumab treatment Furthermore,
145 (95.4%) gave the correct indication for panitumu-mab as being for the treatment of patients with mCRC and confirmed wild-type RAS tumour status (Table 2)
Table 1 Oncologist characteristics in the physician survey and medical records review studies
( N = 301) Round 3( N = 152) Total( N = 453) Rounds 1 & 2( N = 79) Round 3( N = 40) Total( N = 119) Country, n (%)
Type of institution, n (%)
Size of institution, no of inpatient beds a 493.6 (465.6) 623.9 (434.5) 538.2 (475.6) 316.9 (525.4) 640.2 (570.7) 422.6 (559.0)
No of years ’ experience as a practising oncologist specialising in mCRC
Median (Q1 –Q3) 11.0 (7.0 –16.0) 12.0 (8.0 –18.0) 12.0 (7.0 –17.0) 15.0 (10.0 –20.0) 14.0 (10.0–17.5) 15.0 (10.0–20.0)
No of patients with mCRC treated by the oncologist in the previous 3 months
Median (Q1 –Q3) 40.0 (25.0 –70.0) 40.0 (30.0–60.0) 40.0 (25.0–65.0) 36.0 (20.0–70.0) 28.0 (20.0–40.0) 30.0 (20.0–50.0)
No of patients with mCRC treated with panitumumab in the last 6 months
mCRC metastatic colorectal cancer, NR not recorded, Q quartile, SD standard deviation
a
Rounds 1 and 2 of the study participants were asked only about the number of inpatient beds in their facility, which could have led to confusion regarding whether they should give the total number of beds in the hospital or in their oncology department The survey was amended in Round 3 to prevent this
Trang 5When asked about tumour mutation testing, 48
(31.6%) oncologists indicated that all of their patients
who were assessed for tumour mutation status in the
preceding 6 months of routine clinical practice
under-went full RAS testing However, 46 (30.3%) oncologists
indicated that their patients were tested for KRAS
tumour mutation status only, and the remaining 58
(38.2%) indicated that while some patients were tested
forRAS tumour mutation status, some patients had only
been tested forKRAS tumour mutation status
Prior to prescribing panitumumab in the past 6 months
of routine clinical practice, 143 (94.1%) oncologists
re-ported that they were aware of their patients’ tumour
RAS mutation status Only eight (5.3%) of the
participat-ing oncologists responded that they were not aware of
their patients’ RAS tumour status before initiating
pani-tumumab treatment, and one oncologist gave a‘not sure’
response to the question (Table 2) Further to this, 19
(12.5%) oncologists responded that they had, in the past
6 months of routine clinical practice, administered
pani-tumumab to patients, despite those patients having
mu-tant or unknown RAS tumour status (Table 2) Of 13
(8.6%) oncologists who reported that they had
adminis-tered panitumumab to patients with a known RAS
tumour mutation, the most common reasons given for
this action were ‘patient’s status or medical condition’
(n = 10; mainly observed as 'good patient condition) and
‘patient request’ (n = 3) Of seven (4.6%) oncologists
who reported that they had administered panitumumab
to patients with an unknown RAS tumour status, the
most common reason given for this action was‘time to
obtain test results’ (n = 4) with reported times varying
up to a month
Of the 105 (69.1%) oncologists who had prescribed panitumumab simultaneously with oxaliplatin-containing chemotherapy, 97 (92.4%) confirmed that they had in the past 6 months of routine clinical practice only admin-istered panitumumab simultaneously with oxaliplatin-containing chemotherapy to patients with confirmed wild-type RAS tumour status (Table 2)
In total, 118 (77.6%) of the oncologists surveyed in Round 3 recalled having received educational material regardingRAS testing, in the form of a physician educa-tion brochure detailing the importance of testing for RAS status
MRR
For Round 3 of the MRR, 95 oncologists were approached and sent the initial screening questionnaire Of these, 63 (66.3%) responded to the screening questionnaire and 40 (42.1%) were eligible and agreed to participate in the study and provide anonymised information from their patients’ medical records (Fig 1) Over half of the oncologists were from France and Germany; the rest were from Italy, Spain, the Czech Republic, Belgium, Sweden, Denmark and the Netherlands (Table 1)
The types of institutions with the highest number of participating oncologists were, in descending order, gen-eral or regional hospitals (n = 12; 30.0%), private clinics and hospitals (n = 11; 27.5%) and university or teaching/ training hospitals (n = 7; 17.5%) The median duration of experience as a practising oncologist specialising in
Table 2 Outcomes ofRAS testing in Round 3 of the physician survey study
(95% CI)
(100.0 –100.0) Aware of the correct indication for panitumumab for treatment of patients
(92.1 –98.7) Aware of patients ’ tumour RAS status prior to initiation of panitumumab
treatment in the past 6 months of routine clinical practiceb
143 (94.1) (90.3 –97.8) Administered panitumumab to only patients with mCRC and wild-type RAS
(80.7 –91.7) Subset of oncologists who administered panitumumab concurrently with
oxaliplatin-containing chemotherapy
( N = 105) Administered panitumumab with concurrent oxaliplatin-containing
chemotherapy to only patients with mCRC and wild-type RAS in the
past 6 months of routine clinical practiced
97 (92.4) (87.3 –97.5)
CI confidence interval, mCRC metastatic colorectal cancer
a
Six oncologists responded for treatment of patients with mutant RAS tumours and one oncologist gave a ‘not sure’ response
b Eight oncologists were unaware of patients’ tumour RAS status before initiation of panitumumab treatment and one oncologist gave a ‘not sure’ response
c
Nineteen oncologists had administered panitumumab to patients with mCRC and mutant RAS tumours or with unknown tumour RAS status, and two oncologists gave a ‘not sure’ response
d
Eight oncologists had administered panitumumab with concurrent oxaliplatin-containing chemotherapy to patients with mCRC and mutant RAS tumours or with tumour RAS status unknown
Trang 6mCRC among participants was 14.0 years (IQR 10.0–
17.5 years), and the median number of patients with
mCRC who they had treated in the 3 months before
their participation in the MRR was 28.0 (IQR 20.0–40.0)
(Table 1)
The participating oncologists provided data for a total
of 131 patients, who were then included in Round 3 of
the MRR The majority of these patients were male with
a median age of 65.0 years (IQR 56.0–73.0 years) In
addition to panitumumab treatment, 71 (54.2%) patients
were also receiving concurrent oxaliplatin-containing
chemotherapy (Table 3)
Overall, 109 (83.2%) patients had been tested for RAS
mutation status and 22 (16.8%) had only been tested for
KRAS mutation status However, before their first dose
of panitumumab all 131 patients were tested for tumour
mutation status and had tumours with either a
con-firmed wild-type RAS or KRAS mutation status Of the
71 patients who were treated with concurrent
oxaliplatin-containing chemotherapy, all had tumours
with either a confirmed wild-type RAS or KRAS
muta-tion status before their first dose of panitumumab
(Table 4)
Of the 28 pathology laboratories that were identified
by participating oncologists in Round 3 of the MRR, 17
(60.7%) responded to the follow-up survey regarding
their testing practices All 17 laboratories had reportedly
participated in at least one quality assurance (QA)
scheme: seven (41.2%) had participated in the Directory
of Molecular Genetics External Quality Assessment
(EQA) Schemes; seven (41.2%) in a national or regional
QA scheme (such as the Gen&Tiss scheme in France);
six (35.3%) in the European Society of Pathology scheme;
three (17.6%) in the United Kingdom National External
Quality Assessment Service; two (11.8%) in the Quality
Assurance Initiative of the German Society of Pathology;
one (5.9%) in the College of American Pathologists; and
one (5.9%) in another type of QA scheme Of the 17 la-boratories surveyed, 16 (94.1%) used a CE-marked or otherwise validated RAS mutation detection method (validation was performed in house, as per the Inter-national Organisation for Standardization 15,189 standard)
Discussion
Recent changes to the prescribing guidelines for anti-EGFR mAbs (panitumumab and cetuximab) requireRAS tumour genotyping to be carried out for patients with mCRC prior to the initiation of these therapies These revisions have highlighted the need to gain a better un-derstanding on prescribing oncologists’ awareness of these changes The physician survey and MRR, the third rounds of which have been described here, were carried out to assess physicians’ knowledge of the updated indi-cation for panitumumab treatment, following the changes to the label fromKRAS to RAS mutation testing [18]
In Round 3 of the physician survey, all oncologists who participated were aware thatRAS testing should be performed before their patients’ first dose of panitumu-mab Further to this, nearly all of the oncologists (95.4%) also correctly identified that panitumumab is indicated for the treatment of mCRC in patients with confirmed wild-typeRAS tumour status These findings are consist-ent with the results of Rounds 1 and 2 of the physician survey, conducted in 2012–2013 before the latest label changes for panitumumab, where the majority (99.0%) of participants correctly identified thatKRAS testing should
be performed in patients with mCRC and confirmed wild-type KRAS tumours, in accordance with the then-correct indication for panitumumab [18]
In Round 3 of the MRR, all of the patients whose medical records were investigated had a confirmed wild-type tumour status before the initiation of panitumumab
Table 3 Patient demographics in the medical records review study
SD standard deviation
a
Received oxaliplatin-containing chemotherapy during the interval from 7 days before the date of the first dose of panitumumab until 7 days after the last dose
Trang 7treatment, although a minority (16.8%) were only tested
for KRAS mutation status All patients included in the
MRR who were treated with panitumumab and
concur-rent oxaliplatin-containing chemotherapy had confirmed
wild-type tumour status, again though a small number
(9.9%) were only tested forKRAS mutation status
Nineteen of the oncologists (12.5%) who participated
in Round 3 of the physician survey confirmed that they
had administered panitumumab to at least one patient
with mCRC and mutant or unknownRAS tumour status
within the 6 months prior to completing the survey The
reasons given for these treatment decisions indicate that
there may be clinical considerations relating to a
pa-tient’s clinical status, the practicalities of RAS testing, or
the possibility that in later lines of therapy, patients and
physicians may resort to treatments which are either not
included in, or deviate from, guidelines This suggests
there is still a need for physician education which would
enable each of these obstacles to be easily overcome and
lead to improved practice so that all mCRC patients
have a confirmed wild-type RAS tumour status before
starting treatment with panitumumab
In contrast to the physician survey, Round 3 of the
MRR found that all patients studied had a confirmed
wild-type tumour status prior to the initiation of
panitumumab treatment; however, this was accounting
for both KRAS and RAS testing, and the former was
not explicitly asked about in the physician survey,
which may in part explain the disparity Furthermore,
the physician survey and MRR results are not directly
comparable, due to differences in the question
regard-ing off-label prescription of panitumumab (the
phys-ician survey assessed the percentage of physphys-icians
who prescribed off-label to at least one patient in the
last 6 months, and the MMR assessed the percentage
of patients who were prescribed off-label
panitumu-mab) These results were, again, broadly consistent
with the combined results from Rounds 1 and 2 of
both studies, which found that 5.0% of oncologists
surveyed had treated a patient with panitumumab
when they had either an unknown or mutant KRAS
status while the MRR found that only 2.3% of
pa-tients had received panitumumab without having a
confirmed wild-type KRAS status [18]
As other studies have shown, a minority of laborator-ies in Europe have continued to useKRAS testing since June 2013, despite the panitumumab label change [19] This is important to note, both because of the update to the indication for anti-EGFR therapies and also because KRAS mutation testing is less sensitive than full RAS testing [20] However, a further examination of the data from Round 3 of the MRR identified that 18 of the 22 samples tested forKRAS only had a test report date be-fore the start of 2014, suggesting that they may have been carried out either before or immediately after the change to the prescribing guidelines Additionally, in Round 3, each tumour sample was classified as having been tested for eitherRAS or KRAS based exclusively on the information recorded in the oncologist notes; the classification was not based on the specific exons and codons tested by the pathologist as this is often not re-corded As this is information which could not have been validated using another data source, it is possible there was some degree of misclassification with samples classified asRAS tested but in practice not tested for all exons 2, 3, 4 ofKRAS and NRAS
Despite efforts to obtain a higher response rate follow-ing the first two rounds of the study, the response rate for Round 3 was low (5.9%) This could potentially intro-duce selection bias as shown by the relatively high vol-ume of mCRC patients treated by the participating oncologists (median of 40 in the past 3 months) [21, 22] For the MRR study, a similarly low response rate was observed amongst oncologists in Round 1 A higher re-sponse rate was observed in Rounds 2 and 3 after chan-ging to a more targeted methodology without this impacting the study results [18] Finally, response rates
of <10% are not uncommon for knowledge physician surveys [23]
As has been described elsewhere,RAS testing methods have been refined considerably over the last five years [24–26], and the results of Round 3 of the MRR are in agreement with this, showing that nearly all (94.1%) of the pathology laboratories surveyed regarding their RAS testing practices reported using a CE-marked or other-wise validated RAS mutation detection method and that all had participated in at least one QA scheme However, there is still clear need for improvement, potentially via
Table 4 Outcomes ofKRAS/RAS testing in Round 3 of the medical records review study
Wild-type mutation status test result confirmed prior to first dose of panitumumab 109 (100.0) 22 (100.0) 131 (100.0) Subset of patients treated with concurrent oxaliplatin-containing therapy RAS (N = 64) KRAS (N = 7) Total ( N = 71)
Wild-type mutation status test result confirmed prior to first dose of panitumumab 64 (100.0) 7 (100.0) 71 (100.0)
Trang 8additional education, to ensure that all oncologists and
pathologists treating patients with mCRC are
imple-menting fullRAS testing
Conclusions
The results presented here from Round 3 of the
phys-ician survey demonstrate that there is a high level of
knowledge and awareness among practising oncologists
regarding the need for full RAS testing in patients being
considered for panitumumab treatment The generally
high awareness observed in the physician survey is also
confirmed to an extent by Round 3 of the MRR, which
provided insight into how this knowledge is being
ap-plied in routine clinical practice, and showed that the
majority of patients are being tested forRAS tumour
sta-tus before treatment initiation, but highlighted the fact
that some patients are still only being tested for KRAS
mutation status It is important to underline that the use
of panitumumab in patients with mutant or unknown
RAS tumour status may be detrimental to patient
out-comes and therefore, it is essential that oncologists
fol-low the correct indication Despite the change in
guidelines after the introduction of the more
compre-hensive RAS testing, the Round 3 results showed that
oncologists’ awareness and adherence to guidelines have
remained high over time despite the change in
guide-lines and the introduction of the more comprehensive
RAS testing
Additional files
Additional file 1: Interview guide/questionnaire used for the telephone
interviews (DOCX 61 kb)
Additional file 2: List of all Ethical committees that approved the study.
(DOCX 16 kb)
Abbreviations
CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor;
EQA: External quality assessment; EU: European union; FOLFIRI: 5-fluorouracil/
folinic acid + irinotecan; FOLFOX: 5-fluorouracil/folinic acid + oxaliplatin;
IQR: Interquartile range; mAb: Monoclonal antibody; mCRC: Metastatic
colorectal cancer; MRR: Medical records review; QA: Quality assurance
Acknowledgements
The authors would like to thank and acknowledge the following for their
contributions to the two studies and this article: Rachel Bowman BSc and Jenny
Gandhi MSc (Amgen Ltd.) for statistical programming support; Paula Harding
BSc RGN (Amgen Ltd.) for study management support; Adelphi Research for
conduct and data management of the physician survey study; Quintiles for data
management of the MRR study; and Adelphi Communications Ltd for editorial
assistance and support (funded by Amgen Ltd.).
Funding
Both of these studies were funded by Amgen Ltd Amgen was also involved
in the study design, data collection and analysis, decision to publish and
preparation of the manuscript They also provided funding for medical
Availability of data and materials Amgen engages in collaborative research projects with external researchers
to further clinical research and advance public health by addressing new scientific questions of interest Any external researcher may submit a data sharing request to Amgen related to this manuscript, 'Panitumumab use in metastatic colorectal cancer and patterns of RAS testing: Results from a Europe-wide physician survey and medical records review', by sending an email to Datasharing@amgen.com.
Authors ’ contributions GDo, GDe, JHvK and GK conceived and designed the experiments JHvK, JTr,
LM, JTo, ER, PF, GDM, PGA and GA performed the experiments GDo, JB, GDe,
GK, JHvK and PP analysed the data JHvK, GK, JB, LM, JTo, ER, PF, GDM, PGA,
GA, PP, GDo, GDe and JTr contributed to this manuscript All listed authors have reviewed and approved the final manuscript, and have consented to its publication here.
Ethics approval and consent to participate The study protocols and informed consent forms (ICFs) were reviewed and approved by the local Institutional Review Board or Ethical Review Board and Regulatory Authority, as applicable in each country, before the studies began [18] All ethical committees (ECs) who approved the study are listed in Additional file 2.
As agreed with the ECs in France and the Netherlands, signed ICFs were not required, only verbal informed consent was needed (recorded in the patient ’s file) EC approval was not required in Denmark [27], but a signed ICF was required and obtained at all Danish sites.
Prior to Round 3 of the study, a protocol amendment and associated documents were submitted and approved using the same process Consent for publication
No further patient consent was sought, as this manuscript contains no details pertaining to individual participants.
Competing interests JHvK has received honoraria and research grants from AMGEN and Merck Serono.
GK is a compensated employee of Amgen Ltd as an Observational Research Senior Manager and a stockholder in Amgen Ltd.
JB provided statistical input into the design and analysis of the studies, as a contract Biostatistician funded by Amgen Ltd., and has no competing interests to declare.
LM has provided a consulting or advisory role and received honoraria, travel, accommodation and expenses from Sanofi, Amgen, Baxter, Lilly and Roche, and has patents, royalties or other intellectual property with Convergance JTo has provided a consulting or advisory role and received honoraria, travel, accommodation and expenses from Amgen, Bayer, Lilly, Roche and Sanofi.
ER has received funding for consultation and presentations from AstraZeneca and Roche.
PF has participated in advisory boards for Amgen and Pfizer and has received honoraria as a speaker for Amgen Ltd., Merck Serono, Astra Zeneca,
F Hoffmann-La Roche and Pfizer.
GDM has no competing interests to declare.
PGA has participated in advisory boards and has received honoraria as a speaker for Amgen, Merck Serono, F Hoffmann-La Roche, Sanofi, Bayer and Pfizer.
GA has received educational grants from Roche, Eli-Lilly, Amgen, Merck, Bayer and Sanofi in the last two years.
PP is a compensated employee of Amgen Ltd as a Clinical Research Study Manager.
GDo is a compensated employee of Amgen Ltd as a Biostatistics Senior Manager and a stockholder in Amgen Ltd.
GDe is a compensated employee of Amgen Ltd as an Oncology Medical Team Lead and a stockholder in Amgen Ltd.
JTr has participated in advisory boards and received honoraria, travel, accommodation and expenses from Amgen, Merck Serono, Roche and Bayer.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
Trang 9Author details
1 Radboud University Medical Center, Nijmegen, Netherlands 2 Amgen Ltd,
Uxbridge, UK 3 Institute Sainte Catherine, Avignon, France 4 Masaryk Memorial
Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech
Republic 5 Curie Institute, Paris, France 6 University and General Hospital,
Udine, Italy 7 Gregorio Marañón Hospital, Madrid, Spain 8 Amgen Ltd,
Cambridge, UK 9 Amgen GmbH, Zug, Switzerland 10 University Hospital,
Frankfurt, Germany.
Received: 14 April 2016 Accepted: 31 October 2017
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